Plasma Proteomic Signature Predicts Myeloid Neoplasm Risk.

Area of Science:

• Hematology
• Proteomics
• Genomics

Background:

• Clonal hematopoiesis (CH) is the presumed origin of myeloid neoplasms (MN).
• Mechanisms driving CH progression to MN and MN clinical risk prediction require further elucidation.
• The human proteome offers insights into genetic and epigenetic regulatory interactions.

Purpose of the Study:

• To investigate if plasma proteomic profiles can predict MN risk.
• To explore if plasma proteomics can inform the mechanisms underlying MN development.
• To assess the utility of plasma proteomics in improving MN risk stratification.

Main Methods:

• Joint characterization of CH and plasma proteomic profiles in 46,237 UK Biobank participants.
• Longitudinal follow-up for MN development (115 cases over 500,036 person-years).
• Cox proportional hazard regression to analyze associations between plasma proteins and MN risk.
• Validation using inherited polygenic risk scores (PRS) in an independent cohort (N=381,485).

Main Results:

• Identified 115 proteins associated with MN risk; 34 (30%) were also linked to CH, enriched for immune system regulators.
• Plasma proteomics significantly improved MN risk prediction (AUC=0.85) compared to clinical factors and CH alone (AUC=0.80).
• PRS analyses indicated identified proteins are likely downstream markers of CH to MN progression pathways, not directly causal.

Conclusions:

• Plasma proteomics enhances the prediction of myeloid neoplasm risk.
• Immune cell regulation plays a crucial role in the progression of clonal hematopoiesis to myeloid neoplasms.
• Multi-omic characterization, including plasma proteomics, holds promise for improved MN risk stratification.